A scientific evaluation of therapies used in the Pediatric ICU (PICU) is essential to build an evidence base that will guide the management of critically ill children. The 26-bed PICU at Arkansas Children's Hospital provides advanced trauma and intensive care to >1500 critically ill infants/children each year in a research driven, academic environment, supported by 8 Pediatric Intensivists, air/ground transport service, and all medical and surgical subspecialties. The P.I. is well-known for his clinical research on alleviating the pain and stress responses of infants and children by opioids or other agents, with participation and leadership of several multicenter clinical trials. The Study Coordinator has a rich background in academic nursing, grants management, coordination of multicenter studies and clinical experience in the PICU. This environment is well-suited for collaborative research with a strong track record of participation in multicenter trials, patient recruitment from a geographically defined area, and established follow-up programs. A randomized controlled trial to evaluate novel therapies for reducing opioid tolerance in ventilated critically ill children is proposed. Aim 1 will investigate the effects of low-dose Naloxone infusions on development of opioid tolerance and opioid withdrawal in PICU patients. Aim 2 will examine the impact of low-dose Naloxone infusions on clinical outcomes such as the need for additional analgesia/sedation , the duration of opioid weaning required and length of PICU stay after extubation. Aim 3 v/ill identify the clinical, pharmacogenomic, neuroendocrine, and neurobehavioral factors associated wii:h susceptibility to opioid tolerance and withdrawal in children. This study further proposes a public-private partnership to evaluate new technology for monitoring sedation in PICU patients. Opioid therapy is perhaps the most common drug therapy leading to PICU complications and warrants an investigation of novel approaches for prevention and treatment. The P.I., Study Coordinator, and Co-Investigators have protected research time, clinical and translational research experience, and the scientific skills to contribute to the proposed Collaborative PCCM Network, together with established educational and training programs for training future investigators.